Role of NADPH oxidase isoforms NOX1, NOX2 and NOX4 in myocardial ischemia/reperfusion injury
Role of NADPH oxidase isoforms NOX1, NOX2 and NOX4 in myocardial ischemia/reperfusion injury
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DOI：
10.1016/j.yjmcc.2013.09.007
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发表时间：
2013-11-01
影响因子：
5
通讯作者：
Jaquet, Vincent
中科院分区：
文献类型：
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作者：
Braunersreuther, Vincent;Montecucco, Fabrizio;Jaquet, Vincent
心肌再灌注损伤是由多种过程介导的，其中包括活性氧（ROS）的增加。本研究的目的是确定导致心肌缺血-再灌注损伤的ROS的潜在来源。为此，我们研究了各种NADPH氧化酶亚型（Nox 1，Nox 2，Nox 4，以及Nox 1/2双敲除）缺陷小鼠的心肌缺血/再灌注病理学。缺血30 min再灌注24 h后，Nox 1-、Nox 2-和Nox 1/Nox 2-小鼠心肌梗死面积显著减小，但Nox 4-缺陷小鼠心肌梗死面积未显著减小。然而，在慢性缺血模型中没有观察到保护作用，这表明在再灌注期间发生了NOX 1和NOX 2介导的氧化损伤。Nox 1和Nox 2缺陷的心肌保护作用与中性粒细胞侵袭的减少有关，但另一方面，在离体灌注心脏（Langendorff模型）中也观察到改善的再灌注损伤，表明炎性细胞不是氧化损伤的主要来源。在Nox 2-，但不是在Nox 1-缺陷的心脏，全球再灌注后的氧化应激明显减少。再灌注过程中的关键信号通路的分析表明不同的心脏保护模式：增加磷酸化的Ala和Erk在Nox 1缺陷小鼠和Stat 3和Erk在Nox 2缺陷小鼠。因此，NOX 1和NOX 2代表了用于控制与冠状动脉疾病中的血运重建相关的再灌注损伤的令人感兴趣的药物靶标。(C)2013爱思唯尔有限公司保留所有权利。
Myocardial reperfusion injury is mediated by several processes including increase of reactive oxygen species (ROS). The aim of the study is to identify potential sources of ROS contributing to myocardial ischemia-reperfusion injury. For this purpose, we investigated myocardial ischemia/reperfusion pathology in mice deficient in various NADPH oxidase isoforms (Nox1, Nox2, Nox4, as well as Nox1/2 double knockout). Following 30 min of ischemia and 24 h of reperfusion, a significant decrease in the size of myocardial infarct was observed in Nox1-, Nox2- and Nox1/Nox2-, but not in Nox4-deficient mice. However, no protection was observed in a model of chronic ischemia, suggesting that NOX1 and NOX2-mediated oxidative damage occurs during reperfusion. Cardioprotective effect of Nox1 and Nox2 deficiencies was associated with decrease of neutrophil invasion, but, on the other hand an improved reperfusion injury was also observed in isolated perfused hearts (Langendorff model) suggesting that inflammatory cells were not the major source of oxidative damage. A decrease in global post-reperfusion oxidative stress was clearly detected in Nox2-, but not in Nox1-deficient hearts. Analysis of key signaling pathways during reperfusion suggests distinct cardioprotective patterns: increased phosphorylation was seen for Ala and Erk in Nox1-deficient mice and for Stat3 and Erk in Nox2-deficient mice. Consequently, NOX1 and NOX2 represent interesting drug targets for controlling reperfusion damage associated with revascularization in coronary disease. (C) 2013 Elsevier Ltd. All rights reserved.